Treatment of Anxiety and Mood Disorders. John T. Walkup, MD Division of Child and Adolescent Psychiatry Weill Cornell Medical College New York, NY

Transcription

1 Treatment of Anxiety and Mood Disorders John T. Walkup, MD Division of Child and Adolescent Psychiatry Weill Cornell Medical College New York, NY

2 Disclosure: John T. Walkup, MD Consultant Advisory Board Speaker s Bureau Research Contract Royalties Pfizer Abbott Lilly X Drug and PBO X Drug X Drug and PBO Shire X Tourette Syndrome Assoc. X X X Oxford Press Guilford Press X

3 Off Label Use Should consider all medication uses discussed as off label unless specifically noted otherwise Case example details changed for confidentiality purposes

4 Anxiety Disorders in Children and Adolescents Specific Phobia Separation Anxiety Disorder Generalized Anxiety Disorder Social Phobia OCD Acute Stress Disorder Post-traumatic stress disorder Panic Disorder

5 Ages of Risk ASDs 0-3 years or later for mild ADHD or later for mild but differential is broader Anxiety 6-12 years Depression years Bipolar and psychosis - > 16 years Disruptive behavior almost anytime

6 Key Features of the Anxiety Disorders Hypervigilant Reactive to novel stimuli Threat bias Avoidance coping Catastrophic reactions Parental accommodation

7 Physical Symptoms Provoked and Spontaneous Anxious children listen to their bodies Headache Stomachache stomach and bowel problems Sick in the morning and can t fall asleep in the evening Frequent urge to urinate or defecate Shortness of breath Chest pain - tachycardia Sensitive gag reflex - fear of choking or vomiting Difficulty swallowing solid foods growth inhibition? Dizziness, lightheaded Tension and tiredness exhausted and irritable after a school day Derealization and depersonalization Avoidance to prevent above physical symptoms

8 Course of anxiety Onset in childhood Prepubertal affective illness Adolescence Intense symptoms burn out Generalized anxiety Poor adaptation and coping easily flooded and overwhelmed (pre-borderline) Some morph to depression Young adulthood

9 Treatment of OCD

10 Serotonin Reuptake Inhibitors FDA Approvals Clomipramine - FDA approved to age 10 OCD Fluvoxamine - FDA approved to age 8 OCD Sertraline - FDA approved to age 6 OCD Paroxetine effective for OCD and SoP Fluoxetine effective for OCD; MDD to age 7 Citalopram No controlled trials in children Escitalopram FDA approved to age 12 for depression Venlafaxine Effective for SoP but + GAD

11 Pediatric OCD Treatment Study - POTS N = 112 Ages 7-17 years 3 sites, 12 weeks CBT, Sertraline, COMB and placebo Pediatric OCD Treatment Study, 2004

12 CY-BOCS ITT Outcomes 30 COMB > CBT = SER > PBO CY-BOCS TOTAL PBO SER CBT COMB 0 Week 0 Week 12 Pediatric OCD Study Team (2004) JAMA.

13 Site x Treatment Interaction SER CBT COMB Penn Duke Pediatric OCD Study Team (2004) JAMA.

14 Treatment of Other Anxiety Disorders

15 Separation Anxiety Disorder Generalized Anxiety Disorder Social Phobia Pharmacotherapy RUPP trial, 2001 Birmaher et al., 2003 CAMS, 2008 Psychotherapy Kendall, 1994 Kendal et al., 1997 Many others

16 Child/Adolescent Anxiety Multimodal Study (CAMS) NIMH-funded SAD, GAD and SoP N= weeks acute phase 6 month follow-up Results COMBO 81% CBT 60% Sertraline 56% PBO 24% Avg age Avg dose ~140 mg/day

17 Future Directions What to do with partial response? Meds and CBT Augmentation strategies Dissemination of CBT Dissemination of good pharmacotherapy How long to treat? Can my child come off medication? Biological markers of treatment response

18 Depression and Bipolar Disorder John T. Walkup, MD Division of Child and Adolescent Psychiatry Department of Psychiatry Weill Cornell Medical College and NewYork-Presbyterian Hospital New York, NY

19 Introduction Evidence Base for Teen Depression Short-term outcomes Long-term outcomes Suicidal behavior

20 Treatment of Depressed Teens Treatment for Adolescents with Depression Study (TADS) Treatment of Resistant Depression in Adolescents (TORDIA) ADAPT Treatment of Adolescent Suicide Attempters (TASA)

21 Antidepressant Trials 2 NIMH-funded Demonstrated efficacy Low placebo response rates Many quality indicators 15+ industry-funded Multiple sites High placebo rates No quality indicators FDAMA exclusivity No investment in outcome

22 Placebo Response in C&A Antidepressant Trials Bridge et al Studies published and unpublished Placebo response correlated with number of sites Baseline severity inverse predictor of placebo response Younger subject had higher PBO response rate

23 e.g. Sertraline Wagner et al., 2003 Pooled data of two multisite trials N=376 (Sites = 63) Ages 6-17 years 10 week, double-blind, placebo controlled trial Drug > placebo CDRS Responder 69% vs. 59% CGI-I Responder 63% vs. 53%

24 What is depression? Lets go back a step Normal human sadness Demoralization Sadness without cause Horwitz and Wakefield Loss of Sadness

25 What is depression? Depression before DSM-III Sadness with cause Sadness without cause Black bile Groundless despondency Melancholy Depression after DSM-III Change in mood Other depressed symptoms Context and quality of mood irrelevant

26 Consequence of DSM-III All unhappiness of sufficient severity can be depression Increase rates of depression Increased psychological care Increased medication use Increased failure rates of conventional treatments Maybe increased use of somatic treatments

27 What is depression? Normal human sadness Common Expectable reaction to certain events Can be severe, if event is severe Time limited, but not episodic - moving on is expected Can progress to an autonomous, excessive and disproportionate sadness

28 What is depression? Demoralization Chronic unhappiness due to adverse circumstances Depressive symptoms, but not anhedonia Can be severe Treated with a change in circumstances

29 What is depression? Sadness without cause Depression with anhedonia Many physical manifestations Disproportionate and unexpected as to cause Mood is distinct from normal sadness Autonomous course unaffected by changes in life circumstances

30 The Depression Severity Assessment Dilemma Depressive symptoms

31 The Depression Severity Assessment Dilemma Depressive symptoms

32 The Depression Severity Assessment Dilemma Severity Threshold for Treatment Depressive symptoms

33 The Depression Severity Assessment Dilemma Severity Threshold for Treatment Depressive symptoms

34 The Depression Severity Assessment Dilemma Severity Threshold for Treatment Depressive symptoms

35 The Depression Severity Assessment Dilemma Severity Threshold for Treatment Depressive symptoms

36 The Depression Severity Assessment Dilemma Severity Threshold for Treatment Depressive symptoms

37 The Depression Severity Assessment Dilemma Severity Threshold for Treatment Depressive symptoms

38 Impact on Clinical Trials

39 Who Should be Enrolled? Potential Range of Severity for Treatment Trials Depressive symptoms

40 Who Should be Enrolled? Range of Severity for Treatment Trials Depressive symptoms

41 Who Should be Enrolled? Range of Severity for Treatment Trials Depressive symptoms

42 Who Should be Enrolled? Range of Severity for Treatment Trials Depressive symptoms

43 Who Should be Enrolled? Range of Severity for Treatment Trials Depressive symptoms

44 Who Should be Enrolled? Range of Severity for Treatment Trials Depressive symptoms

45 Who Should be Enrolled? Range of Severity for Treatment Trials Depressive symptoms

46 Treatment of Adolescents with Depression Study (TADS) JAMA August 18, 2004 N=439 teens at 13 sites Ages years Treatment Comparisons Meds (fluoxetine) Cognitive-behavioral therapy (CBT) Combination of medication + CBT Medical Management with placebo Treatment duration - 12 weeks

47 TADS Response Rates 80% 70% 60% 50% 40% 30% 20% 10% 0% 71% = 61% > 43% = 35% COMB FLX CBT PBO

48 Treatment for Adolescents with Depression Study (TADS) Longer term outcome Week 18 COMB 85% FXT 69% CBT 65% Week 36 COMB 86% FXT 81% CBT 81%

49 ADAPT Trial Goodyer et al N=249 MDD to age 17 years Design Brief intervention (n=164) SSRI vs SSRI + CBT (n=208) Result wk 12 Brief intervention - 25% SSRI 45% SSRI+CBT 43%

50 ADAPT Longer Term Outcomes Total of approximately 80% responded Approx 20% no change or worse by endpoint Approx 10% persistently refractory Some new onset responders between12-28 weeks

51 ADAPT Suicidal Adverse Events No increased events in either arm 15-20% had no baseline risk 45% had no risk at wk 6 65% had no risk at wk 28 No between group differences

52 Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) Trial 334 adolescents with major depression resistant to 8 weeks of SSRI treatment Randomized to one of four treatments: Switch to alternate SSRI (Paroxetine then Citalopram) Switch to alternate SSRI + CBT Switch to venlafaxine Switch to venlafaxine plus CBT 12 week trial Unique context (Brent et al, JAMA 2008;299: )

53 TORDIA Wk 12 Outcomes Results Antidep only - 50% response Combo 60% response Moderators Baseline - Lower depression, anxiety Week 12 lower depression, suicidal ideation, anxiety and family problems

54 TORDIA Adherence Blood levels Low and high did worse Medium did better Pill Counts (>30% of pills remaining) Adherent did better 63% vs. 47% Some 51% had evidence of nonadherence

55 TORDIA: Week 24 Outcomes Week 12 Non-responders didn t do more Less than half stayed on original med < 1/3 did something more with medication <¼ switched to another med Very few switched to a non-ssri/nsri No Li or T3 Augmentation Non-response may require a special intervention to motivate participants for next steps.

56 TORDIA: Week 24 Outcomes Responders tailored their treatment even further between week 12 and 24 Response breeds additional interest in treatment

57 Treatment of Adolescent Suicide Attempters Brent et al., 2009 N= 124 Open trial Results Depression 72% responded Suicidal events 19% Suicide attempts 12% Median time to suicidal event 44 days

58 Summary of Studies Depression outcomes Moderators Suicidal behavior Role of psychotherapy

59 Longer Term Outcomes TADS All active treatment converge 80-85% ADAPT TASA Estimated 80+% responded; 10% persistently refractory 72% response TORDIA 60% remitted The earlier the response the better

60 Moderators Severity Duration Comorbidity Family Issues Drugs and alcohol Adherence

61 Suicide Summary Treatment reduces risk Lack of response increases risk Slow depression response Predictors of poor response Only TADS had a finding supporting a relationship to SSRI treatment

62 Psychotherapy No additional benefit, if depression severe TADS and ADAPT Small additional benefit in resistant dep Protective for suicidal behavior Yes TADS No TORDIA, ADAPT

63 Suicidality Risk Difference for Efficacy Industry-spnsrd MDD (many) % = NNT of 10 Investigator initiated MDD (2) 35% = NNT of 3 OCD % = NNT of 5 Non-OCD anxiety disorders % = NNT of 3 Risk Difference for Suicidality Significant overall -.7% = NNH 0f 143 But not for individual disorders MDD - 0.9%; NNH=100 OCD - 0.5%; NNH=200 non-ocd anxiety disorders - 0.7% NNH=140 Bridge et al., 2007

64 Summary We have come a long way in the past 25 years!! Diagnosis, diagnosis, diagnosis Pick treatments to match the condition Early response breeds good outcomes and engagement in treatment Suicidal behavior risks and outcomes are better understood

65 Bipolar Disorder John T. Walkup, M.D. Division of Child and Adolescent Psychiatry Department of Psychiatry Weill Cornell Medical College New York, NY

66 Diagnostic Issues in BPAD

67 Early-onset BPD % Geller et al., 1998; N= 60 Wozniak et al., 1995; N= Euphoria Irritability Cyclic/Episodic Course

68 Children in a Community Study (Cohen et al., 1993) Do episodic and chronic irritability differ in their associations with psychopathology? Longitudinal epidemiological study (N=776, T1-T3= 8 years) Age Time Time Time

69 Results Episodic irritability (1) associated with: Time 2: BPD, GAD, and phobia Time 3: BPD Chronic irritability (1) associated with: Time 2: ADHD, ODD Time 3: MDD

70 Lessons from Pediatric Bipolar Disorder: Things may not be or become what they seem

71 * Core symptoms + impairment Two studies by Lewinsohn et al. Study youth ages years Prevalence of BP Disorder = 1% (10/1000) Prevalence of Subthreshold = 4.3% (43/1000)* Study 2 (follow up) 893 young adults age years Prevalence of BP Disorder = 2.1% Prevalence of Subthreshold = 5.3%

72 Status at Follow-up Bipolar Status Study 1 Study 2 BPD è Chronic (no remission) 35% BPD è Recurrent episodes 27% SUB è First full episode BPD 2%

73 Status at Follow-up Diagnostic Status Study 1 Study 2 SUB è Anxiety Disorder 13% è Major Depression 41%

74 Bottom Line Episodic but not chronic irritability is a marker for bipolarity Chronic irritability is associated with depression Fear of precipitating a manic episode in the chronically irritable may result in under treatment of depression and anxiety.

75 So What is the Solution?

76 Manic Episode: Hallmark Symptoms Distinct period of abnormal elevated, expansive or irritable mood lasting > 7 days Three of the following if euphoric, four if irritable 1) grandiosity 2) decreased need for sleep 3) distractibility 4) pressured speech 5) flight of ideas/ racing thoughts 6) increased goal-directed activity or psychomotor agitation 7) increased involvement in pleasurable activities with potential for painful consequences Leibenluft et al. 2003

77 Pharmacotherapy for Bipolar Disorder in Children and Adolescents

78 The Bipolar Disorder Treatment Dilemma Threshold for study enrollment What med might work for these people? Manic-like symptoms

79 The Bipolar Disorder Treatment Dilemma Threshold for study enrollment What med might work for these people? Manic-like symptoms

80 The Bipolar Disorder Treatment Dilemma Threshold for study enrollment What med might work for these people? Manic-like symptoms

81 Negative Trials* Divalproex ER - Wagner et al, J Am Acad Child Adolesc Psychiatry 2009; 48(5): Olanzapine - Wagner et al, Am J Psychiatry 2006;163:1-8; Topiramate - DelBello et al, J Am Acad Child Adolesc Psychiatry 2005;44: * Didn t differentiate from placebo

82 Positive Trials Olanzapine - Tohen et al, Am J Psychiatry Oct; 164(10): Risperidone - Hass M, Bipolar Disorders 2009; 11: Aripiprazole - Findling RL et al. J Clin Psychiatry Oct;70(10): Quetiapine - DelBello et al, Presented at AACAP 2007 Annual Meeting, Boston MA Ziprasidone - DelBello et al, Presented at AACAP 2008 Annual Meeting, Chicago IL

83 Treatment of Early Age Mania Study Geller Wash U Luby Wash U Walkup Hopkins and Weill Cornell Joshi and Robb Children s National Axelson Pittsburgh Wagner and Emslie - Texas

84 TEAM Summary Strengths Large study of young BPAD I Required elevated mood or euphoria Well-characterized for mania and comorbid conditions Multistep review of video tapes Open design allowed for entry of more severely ill children Opportunity to assess initial monotherapy as well as add-on and switch strategies Maximized opportunity to respond to monotherapy Challenges/Limitations Some ongoing issues with what prepubertal mania is Blind ratings only at week 8; lack of blind ratings for dropouts and at intermediate treatment steps

85 TEAM Results Treatment naive (6-16 years) Risperidone > Li Risperidone > Divalproex Li = Divalproex Non or partial responders to initial rx Risperidone > Li Risperidone > Divalproex Li = Valproate

86 TEAM Adverse Events Wt gain with all medications Mild metabolic changes w Risp Thyroid changes with Li

87 Summary Much to be pleased about!!!! Efficacious treatment for high prevalence conditions anxiety and depression A ways to go to understand bipolar disorder and what is best for whom Need to simplify and enhance psychological treatments